Measles virus immunization with gamma globulin administered simultaneously with measles virus vaccine



United States Patent MEASLES VlRUS llWMUNIZATlON WITH GAMMA GLOBULIN ADMILJISTERED SIMULTANEOUSLY WITH MEASLES VIRUS VACCINE Eben A. Slater, Buchanan County, Md, assignor to Philips Roxane, Ina, 55t- Eoseph, Mm, a corporation of Delaware No Drawing. Filed Aug. 15, 1951', Ser. No. 131,478

7 Claims. (Cl. 167-78) The present invention relates to a novel method of creating immunity against measles.

In administering gamma globulin to persons who have been exposed to measles, the choice of dose and time of injection are usually based on whether prevention or attenuation is desired. It has been frequently stated that the immunity afforded is only transient if no signs of the disease appear. However, a search of the literature has failed to reveal any substantial data that might support this statemen .Francis L. Black: Inapparent Measles After Gamma Globulin Administration, J.A.M.A., vol. 173: 11831188 (July 16), 1960.

The above statement is based on the idea that if gamma globulin (as used in this specification connotes serum derived measles antibody) is administered too early in the course of the measles infection it will tie up the virus and render it incapable of further multiplication with the consequence that a durable immunity is not achieved.

Heretofore, it was believed that the simultaneous exposure to virulent or partially attenuated virus and gamma globulin was incompatible because the anti-serum would attack the virus and render it ineffective to produce the antibodies necessary for the development of immunity.

It is for the above reason that physicians have practiced over the years the idea of giving gamma globulin several days after exposure to the virus if an active immunity was a desired result.

For the past several years many investigators have attempted to develop a safe measles vaccine. T hecurrently available virus strains, even though partially attenuated, were considered too reactive to be used commercially as vaccines. Most investigators have attempted to further reduce this reactivity by further attenuation, but this has not yet been achieved.

No person skilled in the field of immunology had suggested that gamma globulin be used simultaneously with measles virus as an important part of measles vaccination. And, in fact, when the idea of simultaneous use of virus and gamma globulin was proposed to people highly skilled and practicing in the art of measles vaccination, it was their general attitude that it would not succeed. The present invention is concerned with such a concept.

Therefore an object of this invention is to provide a method of immunizing an animal host against measles.

Another object is to provide a novel vaccine for immunizing against measles.

Other objects and advantages will become apparent from the following description and explanation thereof.

The present invention is concerned with the substantially simultaneous administration of gamma globulin and virulent or attenuated measles virus to develop immunity. The gamma globulin may be administered at the same or a different site from the place of injection of the measles virus. For the purpose of this specification and the appended claims, measles virus is the generic definition for unattenuated and attenuated virus.

The measles virus employed in this invention is the Edmonston strain. This strain has not been attenuated to the level at which it can be administered safely to develop immunity in a host, and consequently up to the present time no worker has seriously considered its use Patented Oct. 8, 1963 for vaccination purposes. Quite unexpectedly, in the face of scientific principle which indicated otherwise, I found that the simultaneous use of gamma globulin with the measles virus could effect surprisingly good results, namely, the serious reactions associated with measles were substantially overcome. The Edmonston strain of measles virus employed for this purpose can be unattenuated or partially attenuated. The attenuation can be accomplished in tissue culture which may contain tissue of the chick embryo, bovine kidney or lung, dog kidney, hamster kidney, mouse kidney, monkey kidney, etc. Orginally the tissue cells are propagated by using sera from a calf, horse, lamb, hog, goat, etc. and a growth medium such as Parkers 199, Karzons, Earles, etc. with or without an antibiotic, such as penicillin, streptomycin, etc. The cells are permitted to grow for at least about 3 to 8 days, preferably 4 to 5 days, and then seeded with the virulent measles virus and placed in growth medium of the type mentioned above, preferably Parkers 199 or Karzons. The tissue culture may be replaced every 5 to 10 days, and the virus may be serially passed for about 1 to 250 times in achieving a state of attenuation suitable for use in vaccination with gamma globulin. If desired, the measles virus may be used without attenuation. However, usually the virus is attenuated by about 10 to 50 serial passages. For inoculation, the virus is free of any sera. The virus is given to the host in an amount of about 10 to 3000 tissue culture infective dose, abbreviated as TCID.

With regard to the gamma globulin, it is preferably administered into the muscle at a different site from the virus. The gamma globulin expectedly reduces the reaction caused by the measles virus, but quite unexpectedly vaccination is also achieved. In general, the gamma globulin is employed in an amount of about .01 to 005 cc. per pound of body weight of the host being immunized. Preferably about 0.02 cc. of gamma globulin per pound of body weight are used.

The virus is introduced into the host in any of several ways, namely, orally, intranasally or parenterally e.g. subcutaneously, intradermally or intramuscularly. The gamma globulin is introduced parenterally by intramuscular injection.

To provide a fuller understanding of the present invention, reference will be had to the following specific examples.

Example 1 Example 2 The experiment of Example 1 was repeated with a 50 pound girl in which 1 cc. of gamma globulin was employed and 1 ml. of measles virus vaccine B attenuated in chicken embryo in accordance with the procedure described by Enders et al., the New England Journal of Medicine, vol. 263, July 28, 1960, pages l53159.

Example 3 In another experiment involving nine children, the vaccination was done as described in Example 1. From daily observations, it was noted that no adverse reaction such as rash or fever occurred and that a very effective im- 3 munity had been induced. No incidence of encephalitis could be determined.

Example 4 1.1 cc. of gamma globulin was inoculated into the buttock of a 55 pound boy and 0.2 ml. of measles virus vaccine A attenuated by the method described in the Enders et al. article supra was administered orally by rubbing onto the buccal mucosa, tongue, oropharynx, and palate of the child by means of a swab. The boy had no untoward etIects from the vaccine or gamma globulin.

I claim:

1. A method of immunizing a person against measles comprising administering an effective dose of a measles virus to said person at one situs substantially simultaneously with the administration of an effective dose of gamma globulin to said person at another situs.

2. The method of claim 1, wherein the virus and the gamma globulin are administered parenterally.

3. A method of immunizing a person against measles comprising orally administering an effective dose of a measles virus to said person substantially simultaneously with the parenteral administration of an elfective dose of gamma globulin to said person.

4. A method of immunizing a person against measles comprising administering intranasally an effective dose of a measles virus to said person substantially simultaneously with the parenteral administration of an effective dose of gamma globulin to said person.

5. A method of immunizing a person against measles, substantially without serious measles reactions, which comprises introducing into said person an effective dose of a live measles virus and separately, but substantially simultaneously, introducing into said person an etfective dose of gamma globulin.

6. The method of claim 5, wherein said dose of gamma globulin is that which develops immunity while substantially overcoming the serious reactions of measles.

7. A method of immunizing a person against measles which comprises introducing into said person an immunologically effective dose of live measles virus, selected from the group consisting of non-attenuated measles virus and attenuated measles virus, and substantially simultaneously administering thereafter a dose of gamma globulin into the muscle of said person at a different site from that of the virus, the dosage of measles antibody being that which develops immunity without serious measles reactions.

References Cited in the file of this patent UNITED STATES PATENTS 1,607,447 Degkwitz Nov. 16, 1926 4 1,967,476 Little July 24, 1934 2,136,131 Green Nov. 8, 1938 2,386,725 Strean Oct. 9, 1945 2,543,215 William et a1. Feb. 27, 1951 OTHER REFERENCES Adams: Comparative Study of Canine Distemper and a Respiratory Disease of Man, Pediatrics, vol. 11, pp. 1527, 1953.

Cabasso et al.: Active Immunization of Ferrets by Simultaneous Injections of Avianized Canine Distemper Vaccine and Anti-Canine Distemper Hyperimmune Serum, Cornell Vet., vol. 43, No. 1, pp. 179-183 (1953).

Enders et al.: Measles Virus: A Summary of Experiments Concerned With Isolation, Properties, and Bc havior, Am. J. Public Health, vol. 47, No. 3, pp. 275- 282, March 1957.

Rake: Measles, Rubella, Exanthein Subitum and Erythema Infectiosum, pp. 741456 of Viral and Rickettsial Infections of Man, edited by Rivers et al., 3rd Ed. Published, 1959, by J. B. Lippincott.

Warren: The Relationships of the Viruses of Measles, Canine Distemper, and Rinderpest, Advances in Virus Research 7, pp. 27-60 (1960).

Warren et al.: The Canine Distemper'Measles Complex. I. Immune Response of Dogs to Canine Distemper, and Measles Viruses, Am. J. Vet. Res, vol. 21, pp. 111- 119, January 19, 1960.

McCrumb et al.: Studies With Live Attenuated Measles Virus Vaccine. I. Clinical and Immunologic Responses in Institutionalized Children, Amer. J. Dis. Child, vol. 101, pp. 689-700, June 1961.

McCrumb et al.: Studies With Live Attenuated Measles Virus Vaccine. III. Development of a Practical Method for Large Scale Immunization," Amer. J. Dis. Child., vol. 101, pp. 708712, June 1961.

Kress et al.: Studies With Live Attenuated Measles Virus Vaccine. II. Clinical and Immunological Responses of Children in an Open Community, Amer. I Dis. Child, vol. 101, pp. 701-707, June 1961.

Protection from measles with gamma globulin and vaccine simultaneously ten years may pass before vaccine alone can do the job, Science News Letter, 79 page 387, June 24, 1961.

Proceedings, International Conference on Measles Immunization, Bethesda, Md, November 79, 1961, published in American Journal of Diseases of Children, vol. 103, No. 3, pp. 205-531, March 1962. 

1. A METHOD OF IMMUINZING A PERSON AGAINST MEASLES COMPRISING ADMINISTERING AN EFFECTIVE DOSE OF A MEASLES VIRUS TO SAID PERSON AT ONE SITUS SUBSTANTIALLY SIMULTANEOUSLY WITH THE ADMINISTRATION OF AN EFECTIVE DOSE OF GAMMA GLOBULIN TO SAID PERSON AT ANOTHER SITUS. 